Polatuzumab vedotin (Polivy™; Genentech/Roche) in combination with bendamustine (Treanda®; Cephalon/Teva Pharmaceutical) and rituximab (Rituxan®; Genentech/Roche) shows encouraging rates of complete response (CR) among patients with transplantation-ineligible, relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

This conclusion is based on study results from a phase Ib/phase II trial published in Journal of Clinical Oncology. [1]

Diffuse large B-cell lymphoma is a cancer of B cells, a type of white blood cell responsible for producing antibodies. It is the most common type of non-Hodgkin lymphoma (NHL) among adults, with an annual incidence of 7–8 cases per 100,000 people per year. The disease occurs primarily in older individuals, who are, on average, 70 years of age when they are diagnosed with the disease. The disease can, however, also occur in children and young adults in rare cases.

Signs and symptoms
DLBCL is the most common type of lymphoma, an aggressive form of cancer that originate in the lymphatic system and can arise in virtually any part of the body. The first sign of this illness is typically the observation of a rapidly growing mass, which is sometimes associated with fever, weight loss, and night sweats.

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Treatment options
Diffuse large B-cell lymphoma is usually curable, however, when treatment fails, the long-term prognosis is poor. Although imprecise, imaging using CT or interim PET (iPET) scans are used to monitor patients during and after treatment.

While rituximab-based chemoimmunotherapy regimens are the conventional standard of care followed by conditioning and autologous or allogeneic stem cell transplantation (SCT) in eligible patients, relapsed/refractory diffuse large B-cell lymphoma represents an area of high unmet need in non-Hodgkin’s lymphoma (NHL) due to the poor outcomes with current salvage treatment.*

Transplantation-ineligible patients with relapsed/refractory DLBCL generally limited treatment options and overall poor treatment outcomes. There are also limited treatment options. As a result, there is a great need to develop novel agents to meet the unmet medical needs of these patients.

Polatuzumab vedotin, an antibody-drug conjugate or ADC, targets CD79b, a surface immunoglobulin expressed on nearly all B-cell surfaces.

The conditionally approved drug contains a humanized monoclonal antibody (mAb) targeting B-cell antigen receptor complex-associated protein beta chain (CD79b) conjugated to the synthetic dolastatin 10-analog microtubule-disrupting monomethyl auristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease-cleavable peptide linker (valine–citrulline; Maleimidocaproylvaline-citrulline-p-aminobenzoyloxycarbonyl or MC-VC-PABC). The advantage of the citrulline-valine (VC) linker is that it is highly stable in plasma.[2][3]

The randomized phase II trial also demonstrated that the combination of polatuzumab vedotin with bendamustine and rituximab reduced the risk for death by more than half compared with bendamustine and rituximab alone.

The study showed improved complete response rates, Progression-free Survival (PFS) and Overall Survival (OS), compared with bendamustine and rituximab alone as well a number of patients reaching durable control without the need for further therapy.

The researchers also assessed the safety of polatuzumab vedotin combined with bendamustine and rituximab and a separate combination in which rituximab was replaced by obinutuzumab (Gazyva®, Genentech/Roche). Both parts of the Phase IIb part of these safety assessments included 6 patients.

Overall, the study included an expansion cohort of 21 patients treated with polatuzumab vedotin plus bendamustine and obinutuzumab and a cohort of 80 patients randomly assigned to polatuzumab vedotin combined with bendamustine and rituximab (n = 40; median age, 67 years; 70% men) or bendamustine and rituximab alone (n = 40; median age, 71 years; 62.5% men). Thirty-nine patients per arm received treatment.

In the study, patients received 90 mg/m² IV bendamustine on days 2 and 3 of cycle 1 and days 1 and 2 of subsequent cycles. They also received either 375 mg/m² IV rituximab on day 1 of each cycle or 1,000 mg/m² IV obinutuzumab on days 1, 8 and 15 of cycle 1 and on day 1 of subsequent cycles.

Patients treated with polatuzumab vedotin received 1.8 mg/kg on day 2 of cycle 1 and on day 1 of subsequent cycles. Treatment continued for up to six 21-day cycles.

The researchers concluded that polatuzumab vedotin combined with bendamustine and rituximab resulted in a significantly higher Complete Response (CR) rate and reduced the risk of death by 58% compared with bendamustine and rituximab in patients with transplantation-ineligible R/R DLBCL.

Note

* Although their current use is restricted to third and subsequent lines of therapy, the anti-CD19 CAR T-cell therapies axicabtagene ciloleucel (Yescarta®; Gilead/Kite) and tisagenlecleucel (Kymriah®; Novartis) have expanded treatment options for patients with DLBCL. But despite the evolving treatment landscape, a significant unmet medical need remains in the treatment of relapsed/refractory diffuse large B-cell lymphoma due to the limited availability of effective treatment options.

References
[1] Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma [published online ahead of print, 2019 Nov 6]. J Clin Oncol. 2019; JCO1900172. doi:10.1200/JCO.19.00172
[2] Hofland P. Phase I Study Supports Therapeutic Potential of Polatuzumab Vedotin in non-Hodgkin Lymphoma. ADC Review / Journal of Antibody-drug Conjugates, April 30, 2015 [Article]
[3] Polson AG, Yu SF, Elkins K, et al. Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma. Blood. 2007;110:616-623. [Article]